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Cyclin‐dependent kinase 9–cyclin K functions in the replication stress response
Author(s) -
Yu David S,
Zhao Runxiang,
Hsu Emory L,
Cayer Jennifer,
Ye Fei,
Guo Yan,
Shyr Yu,
Cortez David
Publication year - 2010
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/embor.2010.153
Subject(s) - microbiology and biotechnology , kinase , cyclin dependent kinase complex , replication (statistics) , cyclin a , cyclin a2 , cyclin , fight or flight response , biology , cyclin d , cancer research , chemistry , genetics , cell cycle , protein kinase a , cyclin dependent kinase 2 , virology , cancer , gene
Cyclin‐dependent kinase 9 (CDK9) is a well‐characterized subunit of the positive transcription elongation factor b complex in which it regulates transcription elongation in cooperation with cyclin T. However, CDK9 also forms a complex with cyclin K, the function of which is less clear. Using a synthetic lethal RNA interference screen in human cells, we identified CDK9 as a component of the replication stress response. Loss of CDK9 activity causes an increase in spontaneous levels of DNA damage signalling in replicating cells and a decreased ability to recover from a transient replication arrest. This activity is restricted to CDK9–cyclin K complexes and is independent of CDK9–cyclin T complex. CDK9 accumulates on chromatin in response to replication stress and limits the amount of single‐stranded DNA in cells under stress. Furthermore, we show that CDK9 and cyclin K interact with ataxia telangiectasia and Rad3‐related protein and other checkpoint signalling proteins. These results reveal an unexpectedly direct role for CDK9–cyclin K in checkpoint pathways that maintain genome integrity in response to replication stress.